Apo-Gefitinib

Gefitinib.

Each tablet contains 250 mg gefitinib.
Chemical Name: N-(3-Chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine.
Molecular Formula and Molecular Mass: C₂₂H₂₄ClFN₄O₃; 446.91 g/mol.
Physicochemical Properties: Gefitinib is a white to off-white powder. Gefitinib is a free base. The molecule has pKa's of 5.4 and 7.2 and therefore ionizes progressively in solution as the pH falls. Gefitinib can be defined as sparingly soluble at pH 1, but is practically insoluble above pH 7, with the solubility dropping sharply between pH 4 and pH 6. In non-aqueous solvents, gefitinib is freely soluble in glacial acetic acid and dimethylsulphoxide, soluble in pyridine, sparingly soluble in tetrahydrofuran, and slightly soluble in methanol, ethanol (99.5%), ethyl acetate, propan-2-ol and acetonitrile.
Excipients/Inactive Ingredients: In addition to the active ingredient gefitinib 250 mg, each tablet contains the following non-medicinal ingredients: amino methacrylate copolymer, colloidal silicon dioxide, crospovidone, ferric oxide red, magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.

Pharmacology: Mechanism of Action: Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). EGFR is expressed on the cell surface of many normal cells as well as cancer cells. Increased EGFR signalling can drive tumour growth through the activation of pathways that are crucial to proliferation, invasion, angiogenesis, metastasis and inhibition of cell death.
Mutations in the tyrosine kinase domain of the EGFR gene are only found in tumour cells and increase the dependency of these tumour cells to the intercellular signalling cascades that result in the promotion of tumour cell growth, blocking of apoptosis, increasing the production of angiogenic factors and facilitating the processes of metastasis.
In patients whose tumour contains an activating mutation of the EGFR-tyrosine kinase (TK), gefitinib binds to the EGFR TK domain with high specificity and affinity, resulting in potent inhibition of the over-active signalling pathways which can lead to tumour shrinkage.
Resistance: Most NSCLC tumors with sensitizing EGFR kinase mutations eventually develop resistance to IRESSA treatment with a median time to disease progression of 1 year. In about 60% of cases, resistance is associated with a secondary T790M mutation for which T790M targeted EGFR TKIs may be considered as a next line treatment option. Other potential mechanisms of resistance have been reported following treatment with EGFR signal blocking agents including bypass signaling such as HER2 and MET gene amplification and PIK3CA mutations. Phenotypic switch to small cell lung cancer has also been reported in 5 to 10% of cases.
Clinical Trials: A randomized, single dose, blinded, 2-way crossover comparative bioavailability study, conducted under fasting conditions, was performed on healthy male volunteers. The results obtained from 63 volunteers who completed the study are summarized in the following table. The rate and extent of absorption of gefitinib was measured and compared following a single oral dose (1 x 250 mg tablet) of Apo-Gefitinib (gefitinib) 250 mg tablet (Apotex Inc.) and IRESSA (gefitinib) 250 mg tablet (AstraZeneca Canada Inc.). (See Table 1.)

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First-line NSCLC Treatment: IPASS STUDY (D791AC00007): Study demographics and trial design: The efficacy and safety of gefitinib was demonstrated in a randomized, open-label, multicentre, Phase III trial versus carboplatin/paclitaxel doublet chemotherapy in the first-line setting (IPASS). This study was conducted in Asia in patients with locally advanced or metastatic (Stage IIIB or IV) NSCLC of adenocarcinoma histology who were ex-light smokers (ceased smoking ≥15 years ago and smoked ≤10 pack years) or never smokers. A total of 1217 patients from 87 centres in China, Hong Kong, Indonesia, Japan, Malaysia, Philippines, Singapore, Taiwan, and Thailand were studied. The primary efficacy endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective tumour response rate (ORR), safety, quality of life (QoL) and symptom improvement. Statistical adjustment for multiplicity was not performed for secondary and exploratory endpoints.
Demographic and baseline characteristics were well balanced between the two treatment groups (see Table 2).

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Study results: In the primary analysis of PFS in the intent-to-treat (ITT) population (see Table 2), the hazard ratio was not constant over time, with the probability of being progression-free in favour of carboplatin/paclitaxel doublet chemotherapy in the first 6 months, and in favour of gefitinib in the following 16 months. This was likely to be because of the different effect of gefitinib in subgroups defined by EGFR mutation status. EGFR activating mutation status was a strong predictive biomarker for the effect of gefitinib compared to carboplatin/paclitaxel. Patients with activating mutations of the EGFR-TK are referred to as patients with EGFR mutation positive tumours as follows.
Pre-planned exploratory biomarker analyses of 437 patients (36%) with evaluable data for EGFR mutation analysis were conducted.
PFS was significantly longer for gefitinib than carboplatin/paclitaxel in patients with EGFR mutation positive tumours (n=261, HR 0.48, 95% CI 0.36 to 0.64, p<0.0001), and significantly longer for carboplatin/paclitaxel than gefitinib in patients with EGFR mutation negative tumours (n=176, HR 2.85, 95% CI 2.05 to 3.98, p<0.0001).
ORR in patients with EGFR mutation positive tumours treated with gefitinib was 71.2% vs. 47.3% for patients with EGFR mutation positive tumours treated with carboplatin/paclitaxel (OR 2.75, 95% CI 1.654 to 4.60, p=0.0001). ORR in patients with EGFR mutation negative tumours treated with gefitinib was 1.1% vs. 23.5% in patients with EGFR mutation negative tumours treated with carboplatin/paclitaxel (OR 0.04, 95% CI 0.01 to 0.27, p=0.0013).
In patients with EGFR mutation positive tumours, significantly more gefitinib-treated patients experienced an improvement in QoL and lung cancer symptoms vs. carboplatin/paclitaxel (FACT-L total score; 70.2% vs. 44.5%, p<0.0001) (TOI 70.2% vs. 38.3%, p<0.0001) (LCS 75.6% vs. 53.9%, p=0.0003). In patients with EGFR mutation negative tumours, significantly more carboplatin/paclitaxel-treated patients experienced an improvement in QoL and lung cancer symptoms vs. gefitinib (FACT-L total score; 36.3% vs. 14.6%, p=0.0021) (TOI 28.8% vs. 12.4%, p=0.0111) (LCS 47.5% vs. 20.2%, p=0.0002).
An analysis of overall survival (OS) was performed after 954 deaths (78% maturity) in the overall study population, as well as in subgroups by EGFR mutation status (e.g. patients with EGFR mutation positive tumours and EGFR mutation negative tumours). Results of these analyses are shown in Table 3 as well as Figures 1 and 2. (See Table 3 and Figures 1 and 2.)

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When considering the OS data in the IPASS study, it is important to note that the majority of patients had received further systemic therapy following discontinuation of randomized first-line treatment, which is likely to confound assessment of the gefitinib treatment effect. Of the patients with EGFR mutation positive tumours randomized to gefitinib treatment, 68% received platinum-based chemotherapy at some point post-discontinuation of randomized gefitinib, and 64% randomized to carboplatin/paclitaxel received EGFR TKI at some point post discontinuation of carboplatin/paclitaxel.
In the IPASS study, a number of exploratory analyses of PFS, ORR and OS for subgroups were performed, including post-hoc analyses by EGFR mutation subtypes (exon 19 deletions and exon 21 L858R mutations) within the subgroup of patients with EGFR mutation positive tumours. The PFS, ORR and OS data for the comparison of gefitinib vs. carboplatin/paclitaxel were in patients with exon 19 deletions (N=140 patients), PFS HR=0.38 (95% CI 0.26 to 0.56), ORR=84.8% vs. 43.2% [OR 7.23 (95% CI 3.19 to 16.37)] and OS HR=0.79 (95% CI 0.54 to 1.15) (median OS 27.2 months vs. 20.6 months); and in patients with exon 21 L858R mutations (N=111 patients), PFS HR=0.55 (95% CI 0.35 to 0.87), ORR=60.9% vs. 53.2% [OR 1.41 (95% CI 0.65 to 3.05)] and OS HR=1.44 (95% CI 0.90 to 2.30) (median OS 18.7 months vs. 24.6 months). The study was not designed and powered to evaluate the differential PFS, ORR and OS by mutation subtypes, therefore the data should be interpreted in such context with caution.
Pre-treated NSCLC: INTEREST STUDY (D791GC00001): INTEREST was a Phase III, randomized, open-label, parallel-group, international, multicentre trial comparing gefitinib to docetaxel in 1466 patients with locally advanced or metastatic NSCLC who had previously received platinum-based chemotherapy and were eligible for further chemotherapy. Pre-planned exploratory subgroup analysis of 44 EGFR mutation positive patients provides supportive evidence for the approved indication. For patients with EGFR mutations, gefitinib was superior to docetaxel in terms of PFS (HR 0.16, 95% CI 0.05 to 0.49, p=0.0012) and ORR (42.1% vs 21.1%, p=0.00361).
NSCLC - Studies of Gefitinib in Combination with Chemotherapy: Controlled trials (INTACT I and II) with first-line treatment of NSCLC indicated no benefit from the addition of gefitinib to platinum-based combined chemotherapies.
Detailed Pharmacology: Pharmacodynamics: In vitro: ZD1839 was tested using a cloned potassium channel assay (hERG assay) to evaluate its effect upon the Ikr potassium current and was shown to be active in this hERG assay, with an IC₅₀ of 1 mM. Dog Purkinje fibre studies were undertaken to investigate the potential for ZD1839 to affect the cardiac action potential. The results indicate a modest potential to affect re-polarisation at high plasma concentrations. There is some evidence for in vivo effects, in the conscious telemetered dog, however these were not clear even at the highest dose tested.
In vivo: ZD1839 has been administered orally at 5, 50 and 500 mg/kg to rats in studies designed to evaluate its effect on the major functional systems. These included the gastrointestinal (rat, GI transit), respiratory (rat, plethysmography), central nervous (rat, Functional Observation Battery and locomotor activity) and cardiovascular (dog, telemetry, only at 5 and 50 mg/kg) systems.
No effects were seen on intestinal transit. Minimal effects were noted at 50 and 500 mg/kg on the respiratory system (decreases in peak inspiratory and expiratory flows, tidal volume and minute volume); on the central nervous system (slight reduction in motor activity); and on the cardiovascular system (dog telemetry at doses of 50 mg/kg showed slight hypotension).
Because the doses studied are higher than the clinically recommended dose, the effects seen in these studies are not likely to be clinically relevant, but caution is advised.
Pharmacokinetics: In vivo: ZD1839 is well absorbed in rat, dog and man based on measured bioavailabilities of >40% in all species. There is evidence of first pass metabolism and prolonged absorption at high doses in animals.
ZD1839 related radioactivity was well distributed into rat tissues and showed an association with melanin containing tissues; however, levels in the CNS were low. Plasma protein binding ranged from 86 to 94% across the species and is not concentration dependent. ZD1839 binds to both human serum albumin and α-1 acid glycoprotein.
ZD1839 was extensively metabolised with three sites of biotransformation. Circulating metabolite patterns in dog and man were similar and all metabolites measured in human plasma were present in the rat. ZD1839 showed no enzyme induction potential in animals and no appreciable inhibition of human P450 isozymes. In vitro, ZD1839 was predominantly metabolised by CYP3A4.
In all species, ZD1839 related material was primarily excreted in the faeces with <6.5% recovered in urine. Biliary elimination was demonstrated in the rat and enterohepatic recirculation of ZD1839 may occur.
In rat and dog, ZD1839 showed rapid clearance and a high volume of distribution. In man, the volume of distribution was greater than in animals and the half-life consequently longer leading to accumulation. When dose normalised, exposure in humans was greater than in rat and dog, but at chronically tolerated doses the exposures were comparable.
The pharmacokinetic parameters for ZD1839 in animals and man are summarised as follows: See Table 4.

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Pharmacokinetics: The pharmacokinetics of gefitinib have been evaluated in healthy volunteers and in cancer patients following both single and multiple dosing.
Absorption: Following single oral administration to volunteers or to cancer patients, absorption was moderately slow and the mean terminal half-life was 30.5 and 41.0 hours, respectively. In volunteers, gefitinib AUC showed up to a 20-fold range at the same dose level and increased proportionally with dose over the dose range 50 to 250 mg. Between 250 and 500 mg, there was a slightly greater than dose proportional increase in exposure but the maximum degree of non-proportionality observed was only 2-fold. In cancer patients, gefitinib AUC increased with dose over the dose range 50 to 700 mg and showed up to an 8-fold range of values within a dose level.
Daily administration of gefitinib to patients resulted in a 2- to 8-fold accumulation with steady state plasma concentrations achieved within 7 to 10 days. At steady state, plasma concentrations were typically maintained within a 2- to 3-fold range across the 24-hour dosing interval. Population pharmacokinetic data from Trial 0016 showed a mean steady state trough concentration following a 250 mg oral dose of 264 ng/mL (95% CI: 92.2 to 755 ng/mL) with inter- and intra-patient variability of 54 and 21%, respectively.
Mean oral bioavailability of gefitinib was approximately 60% in both healthy volunteers and cancer patients, indicating that it was well absorbed. C_max was typically achieved within 3 to 7 hours after dosing in both groups. Relative bioavailability of gefitinib in volunteers was not altered by food to an extent likely to be of clinical significance. In a trial in healthy volunteers where gastric pH was maintained above pH 5 by co-administration of high doses of ranitidine with sodium bicarbonate, relative bioavailability was reduced by 47%.
Distribution: Mean volume of distribution at steady state of gefitinib is 1600 L in volunteers and 1400 L in cancer patients indicating extensive distribution into tissue. At clinically relevant concentrations of gefitinib, binding (in vitro) to human plasma proteins is approximately 90% with the binding proteins involved being serum albumin and α1-acid glycoprotein.
Metabolism: In vitro data indicate that CYP3A4 is the major P450 isozyme involved in the oxidative metabolism of gefitinib. Three sites of biotransformation have been identified in the metabolism of gefitinib: metabolism of the N-propylmorpholino-group, demethylation of the methoxy substituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group. Five metabolites have been fully identified in faecal extracts and the major component was O-desmethyl gefitinib, although this only accounted for 14% of the dose.
In human plasma, 8 metabolites were fully identified. The major metabolite identified was O-desmethyl gefitinib, which was 14-fold less potent than gefitinib at inhibiting EGFR-stimulated cell growth and had no inhibitory effect on tumour cell growth in mice. It is therefore considered unlikely that it contributes to the clinical activity of gefitinib.
The production of O-desmethyl gefitinib has also been shown, in vitro, to be via CYP2D6. The role of CYP2D6 in the metabolic clearance of gefitinib has been evaluated in a clinical trial in healthy volunteers genotyped for CYP2D6 status. In poor metabolisers (devoid of CYP2D6) no measurable levels of O-desmethyl gefitinib were produced. The range of gefitinib exposures achieved in both the extensive and the poor metaboliser groups were wide and overlapping but the mean exposure to gefitinib was 2-fold higher in the poor metaboliser group. The higher average exposures that could be achieved by individuals with no active CYP2D6 may be clinically relevant since adverse experiences are related to dose and exposure.
Excretion: Gefitinib total plasma clearance is approximately 500 mL/min. Excretion is predominantly via the faeces with renal elimination of drug and metabolites accounting for less than 4% of the administered dose.
Special Populations and Conditions: Paediatrics: There are no pharmacokinetic data in paediatric patients.
Hepatic Impairment: In a phase I open-label study of single dose gefitinib 250 mg in patients with mild, moderate or severe hepatic impairment due to cirrhosis (according to Child-Pugh classification), there was an increase in exposure in all groups compared with healthy controls. An average 3.1-fold increase in exposure to gefitinib in patients with moderate and severe hepatic impairment was observed. None of the patients had cancer, all had cirrhosis and some had hepatitis. This increase in exposure may be of clinical relevance since adverse experiences are related to dose and exposure to gefitinib (see Hepatic Impairment under Precautions).
Gefitinib has been evaluated in a clinical trial conducted in 41 patients with solid tumours and normal hepatic function or, moderate or severe hepatic dysfunction due to liver metastases. It was shown that following daily dosing of gefitinib tablets 250 mg, time to steady state, total plasma clearance and steady state exposure (C_maxss, AUC_24ss) were similar for the groups with normal and moderately impaired hepatic function. Data from 4 patients with severe hepatic dysfunction due to liver metastases suggested that steady state exposures in these patients are also similar to those in patients with normal hepatic function.
Renal Insufficiency: No clinical studies were conducted with gefitinib in patients with severely compromised renal function. Gefitinib and its metabolites are not significantly excreted via the kidney (<4%). A limited number of patients with moderate renal insufficiency (calculated creatinine clearance of 30 to 50 mL/min) participated in the clinical trials. Based on the data from these studies, no safety concerns were raised regarding the use of gefitinib in patients with mild or moderate renal impairment in comparison to patients with normal renal function at baseline. Due to the small number of patients, there is insufficient data to evaluate the safety profile of gefitinib in patients with severe renal impairment.
Toxicology: A standard programme of non-clinical safety evaluation studies of up to 6 months in duration has formed the basis of the support for the clinical development of once daily oral therapy to patients.
The no-effect dose level, after administration of ZD1839 for up to 1 month, is 2 mg/kg/day and over a 6-month period is 1 mg/kg/day. In the 1-month studies, a dose of 40 mg/kg/day produced pathological changes in the ovaries of rats and in the eyes, kidneys and skin of both rats and dogs. Loose faeces were recorded in dogs, with no associated histopathological correlate. Similar changes were detected in the 6-month studies and, in addition in rats, minimal/mild hepatocellular necrosis was also detected, together with increased levels of circulating plasma liver enzymes. These effects showed signs of partial or full reversibility after drug withdrawal. There was evidence of reduced fertility in the female rat at 20 mg/kg/day, as well as slight maternal and fetotoxicity in the rabbit. These changes were all attributed to the pharmacological effects of ZD1839 on EGF-dependent tissues. Reversible abnormalities of atrio-ventricular conduction were also seen in the dog, at 40 mg/kg/day in the 1-month study and at 15 mg/kg/day in the 6-month study.
Preclinical work in guinea pigs indicates that gefitinib may be a potential skin (contact) sensitiser. Results of an in vitro phototoxicity study demonstrated that gefitinib may have phototoxicity potential.
Acute Toxicity: Following a single oral dose of ZD1839 at 2000 mg/kg to rats, there was a 5-day interval prior to the onset of abnormal signs. All animals showed adverse signs, leading to 4 premature deaths in females. The cause of death of 1 of these 4 decedents was a perforated duodenal ulcer. Other compound-related findings were present in tissues of these animals, including the kidneys, liver, skin and upper gastro-intestinal tract. No abnormalities were seen in mice given the same oral dose nor in rats and mice at the maximum achievable dose of 20 mg/kg by the intravenous route. Single oral doses of up to 1000 mg/kg to dogs produced no deaths, but caused adverse effects that had a rapid onset, but were reversible. These effects comprised emesis, diarrhoea, loss of skin tone, reduced blood pressure, reduced appetite, loss of body weight and increased plasma ALT, AST and ALP activities.
Multiple Dose Toxicity Studies: The no effect dose level after administration of ZD1839 to rats and dogs for up to 1 month was 2 mg/kg/day. A dose of 10 mg/kg/day showed only minor changes in red blood cell parameters, plasma protein, and albumin in the 1-month dog study and no adverse effects in the 1-month rat study. A dose of 40 mg/kg/day in the rat for a month produced reversible increases in plasma ALT and AST levels, but with no pathological correlate. There were histopathological changes in the ovaries of rats (reduced corpora lutea) and in the eyes (corneal epithelial atrophy), kidneys (papillary necrosis), and skin of both rats and dogs, all of which showed signs of partial or full reversibility, 4 weeks after drug withdrawal. Loose faeces were recorded in dogs, with no associated histopathological correlate. These changes were attributed to the pharmacological effects of ZD1839. Reversible prolonged PR intervals, with large variations between individual measurements were recorded for 2 out of 12 dogs at 40 mg/kg/day. In addition, one of these two dogs also showed second-degree heart block.
The findings in the 6-month studies were consistent with those detected in the 1-month studies and were similarly attributed to the pharmacological effects of ZD1839. These studies commenced with a high dose of 25 mg/kg/day, however this was not tolerated and the dose level was reduced to 15 mg/kg/day from day 11 in dogs and from week 9 in rats. The no adverse effect dose level, after administration of ZD1839 to rats and dogs for up to 6 months was 1 mg/kg/day. At 5 mg/kg/day, rats and dogs showed skin lesions and the rats had reversible corneal atrophy of the eyes. These eye effects were more evident in both species at 15 mg/kg/day, but still showed signs of recovery. However, at this dose level in dogs, some areas of opacity developed that did not fully recover during the 12-week withdrawal period. Evidence of an effect on liver function was detected in the rat at 5 mg/kg/day; this was more pronounced in both species at 15 mg/kg/day. In addition, in the rat at this dose, there was hepatocellular necrosis, associated with the increases in plasma liver enzyme levels. A single female dog showed evidence of a reversible effect on P-R interval, similar to that seen in the 1-month study, at the 15 mg/kg/day dose level.
Carcinogenicity & Mutagenicity: ZD1839 has been tested for genotoxic activity (mutagenicity) in a series of in vitro (bacterial mutation, mouse lymphoma, and human lymphocyte) assays and an in vivo rat micronucleus test. Under the experimental conditions adopted, there was no evidence demonstrated of genotoxic activity for ZD1839.
A 2-year oral (gavage) carcinogenicity study in rats resulted in a small but statistically significant increased incidence of hepatocellular adenomas in both male and female rats and mesenteric lymph node haemangiosarcomas in female rats at the high dose (10 mg/kg/day) only. The clinical relevance of these findings is unknown. The hepatocellular adenomas were also seen in a 2-year oral (gavage) carcinogenicity study in mice, which demonstrated a small increased incidence of this finding in male mice dosed at 50 mg/kg/day, and in both male and female mice at the highest dose of 90 mg/kg/day (reduced from 125 mg/kg/day from week 22). The effects reached statistical significance for the female mice, but not for the males. The clinical relevance of these findings is unknown.
Reproduction & Teratology: There was, as expected from the pharmacological activity of ZD1839, a reduction in female fertility in the rat at a dose of 20 mg/kg/day. Gefitinib has been found to cross the placenta following oral administration at 5 mg/kg in rats. When administered during organogenesis, there were no effects on rat embryofetal development at the highest dose (30 mg/kg/day); however in the rabbit, there were reduced fetal weights at 20 mg/kg/day and above. There were no compound induced malformations in either species. When pregnant rats that were treated with 5 mg/kg/day from the beginning of organogenesis to the end of weaning gave birth, there was a reduction in the number of offspring born alive. In pregnant rats treated with 20 mg/kg/day, the effects were more severe and included high neonatal mortality. The no observed adverse effect dose level in this study was 1 mg/kg/day. There was evidence that ZD1839 was present in the milk of lactating rats. Following oral administration of carbon-14 labelled gefitinib to rats 14 days postpartum, concentrations of radioactivity in milk were higher than in blood. Levels of gefitinib and its metabolites were 11- to 19-fold higher in milk than in blood, after oral exposure of lactating rats to a dose of 5 mg/kg. These data suggest that there is the potential for adverse effects if ZD1839 was administered to patients who are pregnant or are breast-feeding.

APO-GEFITINIB (gefitinib) is indicated for the first-line treatment of patients with locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC) who have activating mutations of the EGFR-TK (see Monitoring and Laboratory Tests under Precautions).
This indication was based on progression-free survival (PFS). After 78% of trial patients had died, no statistically significant difference in overall survival (OS) was demonstrated with first-line gefitinib compared to the first-line chemotherapy doublet in patients with EGFR mutation positive tumours in the IPASS study (see Pharmacology: Clinical Trials under Actions).
Geriatrics (≥65 years of age): No differences in safety or efficacy were observed between younger and older patients (see Use in the Elderly under Precautions).
Paediatrics (≤16 years of age): APO-GEFITINIB is not indicated for use in paediatric patients, as safety and effectiveness have not been established (see Use in Children under Precautions).

Recommended Dose and Dosage Adjustment: The recommended daily dose of APO-GEFITINIB (gefitinib tablets) is one 250 mg tablet with or without food. Higher doses do not produce a better response and lead to increased toxicity.
Dosage Adjustment: No dosage adjustment is required on the basis of patient age, body weight, gender, ethnicity or renal function. However, data are limited in patients with severe renal impairment (creatinine clearance ≤20 ml/min) (see Pharmacology: Pharmacokinetics: Special Populations and Conditions under Actions) and caution is advised in these patients.
For patients unable to tolerate treatment after a therapy interruption for toxicity, APO-GEFITINIB should be discontinued and another treatment option should be considered.
Dosage Adjustment due to Toxicity: Poorly tolerated diarrhoea: Patients with poorly tolerated diarrhoea (sometimes associated with dehydration) may be successfully managed by providing a brief (up to 14 days) therapy interruption followed by reinstatement of the 250 mg daily dose once toxicity has resolved.
Skin adverse drug reactions: Patients with skin adverse drug reactions may be successfully managed by providing a brief (up to 14 days) therapy interruption followed by reinstatement of the 250 mg daily dose once toxicity has resolved.
Eye symptoms: Patients who develop eye symptoms should be evaluated and managed, including interruption of therapy with APO-GEFITINIB. Reinstatement of the 250 mg/day APO-GEFITINIB dose should be considered when symptoms and eye changes have resolved.
Respiratory symptoms: If patients present with acute onset or worsening of respiratory symptoms such as dyspnoea, cough and fever, APO-GEFITINIB should be interrupted and prompt investigation initiated. If Interstitial Lung Disease (ILD) is confirmed, APO-GEFITINIB should be discontinued and the patient treated appropriately (see Respiratory under Precautions; Adverse Reactions).
Hepatic Impairment: An average 3.1-fold increase in exposure to gefitinib in patients with moderate and severe hepatic impairment due to cirrhosis was observed in a phase I hepatic impairment study (see Hepatic Impairment under Precautions; Pharmacology: Pharmacokinetics: Special Populations and Conditions under Actions). This increase in exposure may be of clinical relevance since adverse experiences are related to dose and exposure to gefitinib.
No dose adjustments are recommended for patients with moderate to severe hepatic impairment (Child Pugh B or C) however, these patients should be closely monitored. No dose adjustments are recommended for patients with elevated aspartate transaminase (AST), alkaline phosphatase or bilirubin due to liver metastases. These patients should be closely monitored for adverse events.
In patients with impaired liver function secondary to liver metastases, gefitinib exposure was similar for patients with moderate hepatic dysfunction compared to normal hepatic function. Data from four patients with severe hepatic dysfunction due to liver metastases suggested that steady state exposures in these patients are also similar to those in patients with normal hepatic function.
In the pivotal trial IPASS, patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 2.5 times upper limit of normal (ULN) with no demonstrable liver metastases or greater than 5 times ULN in the presence of liver metastases were excluded due to potential hepatic concerns associated with the carboplatin/paclitaxel doublet. Consequently, the IPASS study does not contribute any data in this patient population.
Missed Dose: If a dose of APO-GEFITINIB is missed, it should be taken as soon as the patient remembers, as long as it is at least 12 hours before the next dose is due. If it is less than 12 hours to the next dose, the patient should not take the missed dose. Patients should not take a double dose (two doses at the same time) to make up for a forgotten dose.

A limited number of patients were treated with daily doses of up to 1000 mg in phase I clinical trials. An increase in frequency and severity of some adverse reactions was observed, mainly diarrhoea and skin rash.
In one study, a limited number of patients were treated weekly with doses from 1500 mg to 3500 mg (17 patients total / 3 to 4 patients per cohort) and twice weekly with doses from 1500 mg to 2000 mg (6 patients total / 3 patients per cohort). In this study, gefitinib exposure (mean C_max) was approximately 3- to 4-fold that observed on multiple dosing of the therapeutic dose (i.e. 250 mg daily).
The mean QTcB appeared to increase approximately 10 msec at 3 hours postdose in 17 subjects receiving weekly doses of gefitinib tablets. The study was not designed as a 'thorough QTc' study and the QTc data should be approached with caution. No QTcB ≥500 msec was found during the study.
Adverse events were mostly mild to moderate in severity, and were consistent with the known safety profile of gefitinib. The frequency of some AEs, namely nausea, diarrhoea, vomiting, and fatigue appeared to have increased, however the patients enrolled in this study were end stage cancer patients with multiple confounding co-morbidities. Two out of the 6 patients in the twice weekly cohorts (one subject in Cohort 6 on 1500 mg twice weekly; the other in Cohort 7 on 2000 mg twice weekly) developed grade 3 total bilirubin increases however these were not reported as adverse events. Both of these patients had pre-existing liver metastases before start of treatment with gefitinib.
There is no specific treatment in the event of overdose of APO-GEFITINIB. Adverse reactions associated with overdose should be treated symptomatically; in particular, severe diarrhoea should be managed as clinically indicated.
In non-clinical studies, the median lethal oral dose in rats was 2000 mg/kg (approximately 400 times the clinically recommended daily dose in humans on a mg/kg basis). The median lethal oral dose in mice was found to be in excess of 2000 mg/kg.
For management of a suspected drug overdose, seek medical help immediately.

Patients who are hypersensitive to gefitinib or to any ingredient in the formulation. For a complete listing, see Description.

APO-GEFITINIB (gefitinib tablets) should be administered under the supervision of a qualified health professional who is experienced in the treatment and management of patients with cancer.
APO-GEFITINIB should not be used in patients with EGFR mutation negative tumours (see Monitoring and Laboratory Tests under Precautions; Pharmacology: Clinical Trials under Actions).
APO-GEFITINIB has not been studied in patients with severe renal impairment (see Pharmacology: Pharmacokinetics: Special Populations and Conditions under Actions).
Isolated cases of hepatic failure and fulminant hepatitis, including fatalities, have been reported with gefitinib tablets use (see Hepatic/Biliary/Pancreatic: Hepatotoxicity under Precautions).
Gastrointestinal perforation (including cases with a fatal outcome) was observed in patients treated with gefitinib tablets (see Gastrointestinal under Precautions).

Cardiac: No thorough QT/QTc study was performed to rule out the effect of gefitinib on QT prolongation. Routine ECG assessments during clinical trials did not identify any concerns regarding QT prolongation (see Pharmacology: Detailed Pharmacology: Pharmacodynamics under Actions).
Carcinogenicity: Pre-clinical studies have identified a statistically significant increase in hepatocellular adenomas in rats and mice and in mesenteric lymph node hemangiosarcomas in rats. The clinical relevance of these findings is unknown (see Pharmacology: Toxicology: Carcinogenicity & Mutagenicity under Actions).
Drug Interactions: Drugs that cause significant sustained elevation in gastric pH may reduce plasma concentrations of gefitinib and therefore may reduce efficacy (see Interactions).
CYP3A4: Gefitinib is primarily metabolized by CYP3A4.
Substances that are inducers of CYP3A4 activity may increase metabolism and decrease gefitinib plasma concentrations. Therefore, co-medication with CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampicin, barbiturates, or St. John's Wort) may potentially reduce efficacy (see Interactions).
Substances that are inhibitors of CYP3A4 activity (e.g. ketoconazole, macrolides, grapefruit juice) may decrease metabolism and increase gefitinib plasma concentrations. This may be clinically relevant and caution is advised as adverse experiences are related to dose and exposure (see Interactions).
CYP2D6: In vitro studies demonstrate gefitinib has potential to inhibit CYP2D6. In a clinical trial in cancer patients, gefitinib was co-administered with metoprolol (a CYP2D6 substrate). This resulted in a 35% increase in metoprolol exposure. Such an increase might potentially be relevant for CYP2D6 substrates with narrow therapeutic index. When the use of CYP2D6 substrates are considered in combination with gefitinib, a dose modification of the CYP2D6 substrate should be considered, especially for products with a narrow therapeutic window (see Interactions).
Gastrointestinal: Diarrhea, Dehydration and Renal Dysfunction: APO-GEFITINIB use is very commonly associated with diarrhea, nausea, vomiting, stomatitis, and anorexia. Patients should be advised to seek medical advice promptly in the event of developing severe or persistent diarrhoea, nausea, vomiting or anorexia. These symptoms should be managed as clinically indicated as any subsequent dehydration may lead to renal dysfunction if left untreated (see Recommended Dose and Dosage Adjustment under Dosage & Administration).
Gastrointestinal perforation: Gastrointestinal (GI) perforation has been reported uncommonly (0.2%) in patients taking gefitinib, and some cases have been fatal. In most cases this is associated with other known risk factors, including increasing age, concomitant medications such as steroids or NSAIDs, underlying history of GI ulceration, smoking, bowel metastases at sites of perforation, diverticulitis, GI obstructions, or advanced bowel disease. If a diagnosis of GI perforation is confirmed, treatment with APO-GEFITINIB should be interrupted or discontinued.
Haematologic: International Normalised Ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin. Patients taking warfarin should be monitored regularly for changes in Prothrombin Time (PT) or INR (see Interactions).
Two Phase II trials using the combination gefitinib/vinorelbine have been discontinued due to a high incidence of CTC grade 3 and 4 neutropenia. When used in combination, gefitinib aggravated the neutropenic effect of vinorelbine.
Cerebrovascular events have been reported in clinical studies of gefitinib. A relationship with gefitinib has not been established.
Haemorrhage: Throughout the gefitinib lung cancer clinical trials, the incidence of haemoptysis/pulmonary haemorrhage reported on the gefitinib arm has consistently been higher than that reported on the comparator arm (e.g. on IPASS 3.5% vs. 3.1%, gefitinib vs. carboplatin/paclitaxel. Pooled incidence: gefitinib 5.3% vs. placebo 4.4%; gefitinib 5.0% vs. docetaxel 3.5%; gefitinib 3.7% vs. other chemotherapy 2.8%; overall pooled gefitinib incidence: 4.8%). This may in part be explained by the longer duration of treatment on the gefitinib arm.
Epistaxis and haematuria are commonly associated with gefitinib therapy (4.3%).
Hepatic/Biliary/Pancreatic: Hepatotoxicity: Liver function test abnormalities (including increases in alanine aminotransferase, aspartate aminotransferase, bilirubin) have been observed, uncommonly presenting as hepatitis. Isolated cases of hepatic failure and fulminant hepatitis, including fatalities, have been reported with gefitinib use. Therefore, periodic liver function testing is recommended. Gefitinib should be used cautiously in the presence of mild to moderate changes in liver function. Discontinuation should be considered if changes are severe.
Ophthalmologic: Conjunctivitis, blepharitis, and dry eye are commonly seen in patients treated with gefitinib (6.7%) and are generally mild in nature (CTC grade 1). Corneal erosion occurs uncommonly (0.3%), is reversible and sometimes is associated with aberrant eyelash growth. The safety of wearing contact lenses during gefitinib therapy has not been adequately studied.
Patients should be advised to seek medical advice promptly in the event of developing any eye symptoms. Patients presenting with signs and symptoms suggestive of keratitis such as acute or worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmology specialist (see Adverse Reactions). If a diagnosis of ulcerative keratitis is confirmed, treatment with gefitinib should be interrupted, and if symptoms do not resolve, or recur on reintroduction of gefitinib, permanent discontinuation should be considered.
Cases of corneal erosion have been reported during use of gefitinib tablets. Other ocular disorders including abnormal eyelash growth, keratoconjunctivitis sicca or keratitis have been observed with gefitinib treatment. Recent corneal surgery and contact lens wearing are known to be independent risk factors for ocular toxicity including corneal erosion.
These symptoms should be managed as clinically indicated (see Recommended Dose and Dosage Adjustment under Dosage & Administration).
Renal: There have been reports of renal failure secondary to dehydration due to diarrhea, nausea, vomiting and/or anorexia, or associated with pre-renal factors such as concurrent infections or concomitant medications including chemotherapy. In more severe or persistent cases of diarrhea, or cases leading to dehydration, particularly in patients with known risk factors (e.g. renal disease, concurrent vomiting, concomitant medications that impair ability to tolerate dehydration such as NSAIDs and diuretics), gefitinib therapy should be interrupted and appropriate measures taken to intensively rehydrate the patient.
In addition, urea, creatinine and electrolytes should be monitored in patients at high risk of dehydration.
Respiratory: Interstitial Lung Disease (ILD), which may be acute in onset, has been observed in patients receiving gefitinib at an overall incidence of about 1%, and approximately 1/3 of the cases have been fatal (see Clinical Trial Adverse Drug Reactions: Interstitial Lung Disease under Adverse Reactions).
If patients present with worsening of respiratory symptoms such as dyspnoea, cough and fever, gefitinib should be interrupted and prompt investigation initiated. If ILD is confirmed, APO-GEFITINIB should be discontinued and the patient treated appropriately.
The incidence of ILD-type events was 5.8% in patients receiving gefitinib tablets in a post-marketing surveillance study in Japan (3350 patients) (see Clinical Trial Adverse Drug Reactions: Interstitial Lung Disease under Adverse Reactions). In a Japanese Pharmacoepidemiological case-control study (see Clinical Trial Adverse Drug Reactions: Interstitial Lung Disease under Adverse Reactions) in 3159 patients with NSCLC who were followed up for 12 weeks when receiving gefitinib tablets or chemotherapy, the cumulative incidence of ILD (unadjusted for imbalances in patient characteristics) at 12 weeks' follow-up was 4.0% in patients receiving gefitinib tablets and 2.1% in those receiving chemotherapy. The adjusted odds ratio (OR) of developing ILD was 3.2 (95% confidence interval (CI) 1.9 to 5.4) for gefitinib versus chemotherapy. This trial identified the following risk factors for developing ILD (irrespective of whether the patient received gefitinib or chemotherapy): smoking, poor performance status (PS ≥2), CT scan evidence of reduced normal lung (≤50%), recent diagnosis of NSCLC (<6 months), pre-existing ILD, increasing age (≥55 years old) and concurrent cardiac disease. Risk of mortality among patients who developed ILD on both treatments was higher in patients with the following risk factors: smoking, CT scan evidence of reduced normal lung (≤50%), pre-existing ILD, increasing age (≥65 years old), and extensive areas adherent to pleura (≥50%).
Skin: Rash is very common with gefitinib use (57.9%), mainly mild to moderate (CTC grade 1 or 2). Toxic epidermal necrolysis, Stevens Johnson syndrome and erythema multiforme occur rarely (0.04%), and some cases have been fatal (see Recommended Dose and Dosage Adjustment under Dosage & Administration). Cutaneous vasculitis, skin fissures (including rhagades) have been reported. Preclinical work in guinea pigs indicates that gefitinib may be a potential skin (contact) sensitiser. Results of an in vitro phototoxicity study demonstrated that gefitinib may have phototoxicity potential.
Monitoring and Laboratory Tests: Assessment of EGFR Mutation Status: EGFR mutation status must be known prior to starting gefitinib therapy because only patients with an activating mutation of EGFR TK should be treated with gefitinib tablets (see Indications/Uses; Pharmacology: Clinical Trials under Actions). When assessing the EGFR mutation status of a patient, it is important that a well-validated and robust methodology is chosen to minimize the possibility of false negative or false positive determinations.
Clinical characteristics of never smoker, adenocarcinoma histology, and female gender have been shown to be independent predictors of positive EGFR mutation status for both non-Asian and Asian patients. Asian patients also have a higher incidence of EGFR mutation positive tumours (approximately 40% positive rate) than non-Asian patients (approximately 10% positive rate). These clinical characteristics should not be used to guide treatment choice, however they may be helpful in guiding mutation testing. A patient must be defined as EGFR mutation positive before starting gefitinib therapy.
Hematology and Chemistry Assessment: Electrolytes, BUN, creatinine, liver function tests (alanine aminotransferase, aspartate aminotransferase, bilirubin) should be performed at baseline and periodically during gefitinib therapy.
Patients taking warfarin should be monitored regularly for changes in Prothrombin Time (PT) or INR (see Interactions).
Effects on Ability to Drive and Use Machinery: APO-GEFITINIB is not expected to impair a patient's ability to drive or use machines. However, some patients may occasionally feel weak. If this happens, patients should not drive or operate machinery.
Hepatic Impairment: Patients with moderate to severe hepatic impairment (Child Pugh B or C) due to cirrhosis have increased plasma concentrations of gefitinib (see Pharmacology under Actions; Dosage & Administration). An average 3.1-fold increase in exposure to gefitinib in patients with moderate and severe hepatic impairment was observed in a phase I hepatic impairment study. None of the patients had cancer, all had cirrhosis and some had hepatitis. This increase in exposure may be of clinical relevance since adverse experiences are related to dose and exposure to gefitinib.
In the pivotal trial IPASS, patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 2.5 times upper limit of normal (ULN) with no demonstrable liver metastases or greater than 5 times ULN in the presence of liver metastases were excluded due to potential hepatic concerns associated with the carboplatin/paclitaxel doublet. Consequently, the IPASS study does not contribute any data in this patient population.
CYP2D6 Poor Metabolisers: In a clinical trial of healthy volunteers, CYP2D6 poor metabolisers achieved a 2-fold higher mean exposure to gefitinib than in extensive metabolisers. The higher average gefitinib exposures achieved by individuals with no active CYP2D6 may be clinically relevant since adverse experiences are related to dose and exposure.
Use in Pregnancy: There are no adequate and well-controlled studies in pregnant women using gefitinib tablets. Women of childbearing potential must be advised to avoid becoming pregnant. If gefitinib tablets are used during pregnancy or if the patient becomes pregnant while receiving this drug, she should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy. Gefitinib tablets may cause fetal harm when administered to a pregnant woman (see Pharmacology: Toxicology: Reproduction & Teratology under Actions).
Use in Lactation: It is not known whether gefitinib is excreted in human milk, however this is documented to occur in pre-clinical testing (see Pharmacology: Toxicology: Reproduction & Teratology under Actions). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women should be advised against breast-feeding while receiving gefitinib therapy.
Use in Children: In a Phase I/II trial of gefitinib and radiation in paediatric patients, newly diagnosed with brain stem glioma or incompletely resected supratentorial malignant glioma, 4 cases (1 fatal) of CNS haemorrhages have been reported in 45 patients enrolled. A further case of CNS haemorrhage has been reported in a child with an ependymoma from a trial with gefitinib alone. An increased risk of cerebral haemorrhage in adult patients with NSCLC receiving gefitinib has not been established. Gefitinib is not indicated for use in paediatric patients (≤16 years of age), as safety and effectiveness have not been established.
Use in the Elderly: Of the total number of patients participating in the INTEREST and ISEL trials, 37% were aged 65 or older. No differences in gefitinib safety or efficacy effect relative to the comparator were observed between younger and older patients.

Pregnant Women: There are no adequate and well-controlled studies in pregnant women using gefitinib tablets. Women of childbearing potential must be advised to avoid becoming pregnant. If gefitinib tablets are used during pregnancy or if the patient becomes pregnant while receiving this drug, she should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy. Gefitinib tablets may cause fetal harm when administered to a pregnant woman (see Pharmacology: Toxicology: Reproduction & Teratology under Actions).
Nursing Women: It is not known whether gefitinib is excreted in human milk, however this is documented to occur in pre-clinical testing (see Pharmacology: Toxicology: Reproduction & Teratology under Actions). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women should be advised against breast-feeding while receiving gefitinib therapy.

Adverse Drug Reaction Overview: Adverse drug reactions (ADR) found to be associated with treatment with gefitinib tablets are shown in Table 5. The most common adverse drug reactions reported at the recommended 250 mg daily dose, occurring in more than 20% of patients, are diarrhoea, sometimes associated with dehydration and mainly mild or moderate in nature (CTC grade 1 or 2) and less commonly, severe (CTC grade 3 or 4); and skin reactions (including rash, acne, dry skin and pruritus) (Table 5). Approximately 10% of patients had a severe ADR (Common Toxicity Criteria, (CTC) grade 3 or 4). Approximately 3% of patients stopped therapy due to an ADR. The onsets of these ADRs usually occurred within the first month of therapy and were generally mild and non-cumulative as well as reversible.
ADRs have been assigned to the frequency categories in Table 5 where possible based on the incidence of comparable adverse event reports in a pooled dataset from the ISEL, INTEREST and IPASS phase III clinical trials (2462 gefitinib-treated patients) (see Pharmacology: Clinical Trials under Actions). In assigning these frequencies no account was taken of the frequency of reports within the comparative treatment groups or whether the investigator considered it to be related to study medication. The frequency of ADRs relating to abnormal laboratory values is based on patients with a change in baseline of 2 or more CTC grades in the relevant laboratory parameters. (See Table 5.)

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Clinical Trial Adverse Drug Reactions: IPASS STUDY (D791A00007): In IPASS, the most commonly reported adverse events for patients treated with gefitinib tablets were diarrhoea and skin reactions (including rashes/acnes, dry skin and pruritus). Overall, for gefitinib-treated patients with an EGFR mutation positive status, the profile of the most common adverse events was similar to that reported in the overall population and consistent with the known safety profile of gefitinib.
Gefitinib had a more favourable tolerability profile than carboplatin/paclitaxel doublet chemotherapy, indicated by fewer CTC grade 3, 4 or 5 adverse events (31.6% versus 62.5%), fewer dose modifications due to toxicity (16.1% versus 35.2% [carboplatin] / 37.5% [paclitaxel]) and fewer adverse events leading to discontinuation of randomized treatment (6.9% versus 13.6%). In addition, fewer treatment-related adverse events (88.6% versus 96.6%) were reported with gefitinib compared with carboplatin/paclitaxel.
Table 6 summarizes the most commonly reported adverse events observed with gefitinib and carboplatin/paclitaxel therapies in the IPASS trial irrespective of causality. (See Table 6.)

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Formal statistical analyses were performed for ten pre-specified events possibly associated with gefitinib or carboplatin/paclitaxel treatment. This included relevant adverse events of any CTC grade and laboratory parameter values of CTC grade ≥3 (worsenings from baseline only) occurring during the period on randomized treatment (Table 7). Events of rashes/acnes, diarrhoea and CTC Grade ≥3 liver transaminases were reported at a statistically significantly higher incidence in the gefitinib arm. Events of neurotoxicity, and CTC Grade ≥3 haematological toxicity (CTC Grade ≥3 neutropenia, leukopenia, thrombocytopenia, and anaemia) were reported at a statistically significantly higher incidence in the carboplatin/paclitaxel arm. Although nausea and vomiting were included in the group of five events considered possibly associated with gefitinib treatment, the incidence of both was statistically significantly higher in the carboplatin/paclitaxel arm despite premedication. (See Table 7.)

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Interstitial Lung Disease (ILD): In the phase III open-label IPASS trial (see Pharmacology: Clinical Trials under Actions) comparing gefitinib to carboplatin/paclitaxel doublet chemotherapy as first-line treatment in selected patients with advanced NSCLC in Asia, the incidence of ILD-type events was 2.6% on the gefitinib treatment arm versus 1.4% on the carboplatin/paclitaxel treatment arm.
In the INTEREST trial, the incidence of ILD type events was similar for both treatments (gefitinib 10 patients [1.4%] versus docetaxel 8 patients [1.1%]).
In the ISEL trial, the incidence of ILD-type events in the overall population was similar, and approximately 1% in both treatment arms. The majority of ILD-type events reported were from patients of Oriental ethnicity and the ILD incidence among patients of Oriental ethnicity receiving gefitinib therapy and placebo was similar, approximately 3% and 4%, respectively. One ILD-type event was fatal, and this occurred in a patient receiving placebo.
In a Post-Marketing Surveillance study in Japan (3350 patients) the reported rate of ILD-type events in patients receiving gefitinib was 5.8%.
In a Japanese Pharmacoepidemiological case-control study (see Respiratory under Precautions) in patients with NSCLC, the crude cumulative incidence of ILD (unadjusted for imbalances in patient characteristics) at 12 weeks follow-up was 4.0% in patients receiving gefitinib and 2.1% in those receiving chemotherapy and the adjusted odds ratio (OR) of developing ILD was 3.2 (95% confidence interval (CI) 1.9 to 5.4) for gefitinib versus chemotherapy. An increased risk of ILD on gefitinib relative to chemotherapy was seen predominantly during the first 4 weeks of treatment (adjusted OR 3.8; 95% CI 1.9 to 7.7); thereafter the relative risk was lower (adjusted OR 2.5; 95% CI 1.1 to 5.8).
Post-Market Adverse Drug Reactions: The following safety signals have been raised from post-marketing adverse event reports: ILD, pancreatitis, allergic reactions (including angioedema and urticaria), hepatitis and pyrexia.

Overview: Gefitinib showed no enzyme induction effects in animal studies. Human liver microsome studies demonstrated that in vitro gefitinib was not a potent inhibitor of any human CYP enzyme activities. At the highest concentration studied, it produced approximately 50% inhibition of CYP2D6. In a clinical trial in cancer patients, gefitinib was co-administered with metoprolol (a CYP2D6 substrate). This resulted in a small (35%) increase in exposure to metoprolol, which is not considered to be clinically relevant. However, such an increase has potential clinical relevance for CYP2D6 substrates with a narrow therapeutic index and caution is advised when co-administered with gefitinib.
In vitro studies have shown that the metabolism of gefitinib is predominantly via CYP3A4. Co-administration with rifampicin (a known potent CYP3A4 inducer) in healthy volunteers reduced mean gefitinib AUC by 83% of that without rifampicin. Substances that are inducers of CYP3A4 activity may increase metabolism and decrease gefitinib plasma concentrations. Therefore, co-medication with CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampicin, barbiturates, or St. John's Wort) may potentially reduce efficacy.
Co-administration with itraconazole (a potent CYP3A4 inhibitor) resulted in an 80% increase in the mean AUC of gefitinib in healthy volunteers. Substances that are inhibitors of CYP3A4 activity (e.g., azole antifungals such as ketoconazole and itraconazole, macrolide antibiotics such as erythromycin and clarithromycin, protease inhibitors, grapefruit juice etc.) may decrease metabolism and increase gefitinib plasma concentrations. This increase may be clinically relevant as adverse experiences are related to dose and exposure. Therefore, caution should be used when administering CYP3A4 inhibitors with gefitinib.
Co-administration of ranitidine (gastric pH above 5) reduced by 47% the mean gefitinib AUC in healthy volunteers. Drugs that cause significant sustained elevation in gastric pH (histamine H₂-receptor antagonists such as ranitidine or cimetidine; proton-pump inhibitors) may reduce plasma concentrations of gefitinib and therefore potentially may reduce efficacy (see Pharmacology: Pharmacokinetics: Metabolism under Actions).
International Normalized Ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin while on gefitinib therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR.
Drug-Drug Interactions: See Table 8.

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Drug-Food Interactions: Grapefruit juice and other inhibitors of CYP3A4 may decrease metabolism and increase gefitinib plasma concentrations.
Drug-Herb Interactions: St. John's Wort and other inducers of CYP3A4 may potentially reduce the efficacy of gefitinib.
Drug-Laboratory Interactions: Interactions with laboratory tests have not been established.

APO-GEFITINIB (gefitinib tablets) should be stored below 25°C. Protect from moisture.

Targeted Cancer Therapy

L01EB01 - gefitinib ; Belongs to the class of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Used in the treatment of cancer.

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